Cycle 2 project 2

Project 2: Control by purines of neuron-glia interaction during neuroinflammation


PhD student: Jimmy George, India
Home Institute:
Center for Neuroscience and Cell Biology (University of Coimbra); Principle Investigator; Rodrigo A. Cunha
Host Institute: Bordeaux Neurocampus; Principle Investigator: Thierry Amédée

Executive Summary
Neuroinflammation is a feature associated with evolution of brain damage. It is mostly glial cell (astrocytes and microglia) that sustain neuroinflammation, but it is currently unclear if the establishment of a neuroinflammatory status results from intrinsic dysfunction of glial cells or if this is triggered by damaged neurons. Furthermore, the exact nature of glial dysfunction is still poorly characterized: brain damage not only bolsters glial-derived neuroinflammation but is also hampers glial-derived neurotrophic support. Thus, the impact on neuronal circuits of neuroinflammation can be either due to enhanced levels of inflammatory mediators or instead to insufficient neurotrophic support. Attempting to answer these questions meets a major difficulty: our lack of sufficient knowledge to elaborate discriminative protocols able to disentangle the often multi-factorial nature of the relation between neurons, astrocytes and microglia. In fact, there is a clear need for a more detailed characterization of systems controlling neuron-glial interaction.
The global aim of this project is to explore the role of purines in controlling neuron-glia interactions. Since most neurodegenerative diseases involve at their early stages a selective dysfunction and damage of a restricted neuronal region, the synapse, this project will focus on the role of purines in controlling interactions between synapses and microglia.

Purines emerge as promising candidates to mediate the communication between synapses and microglia in the early phases of neurodegenerative conditions. On one hand, ATP is now recognized as a danger signal. Accordingly, ATP is an important activator of microglia. However, the source of ATP acting as a danger signal is unknown. We obtained preliminary data suggesting that distressed nerve terminals are important contributors for ATP release. Future work should address if indeed ATP released from distressed nerve terminals can trigger microglia activation. It also remains to be determined what ATP (P2 receptors) can trigger the activation of microglia cells: two main candidates have emerged, namely P2X4 and P2X7, and the recent availability of trustable knockout mouse lines for each receptor now allows addressing this question.

The second major role for purines lies in the enhanced levels of adenosine that occurs from early stages of neurodegeneration. Adenosine A1 and A2A receptors (A2AR) control information salience in neuronal circuits. Furthermore, A2AR antagonists prevent synaptic modifications, preserving brain function in different animal models of disease. We also found that A2AR (a major controller of all inflammatory cells) controls different features of neuroinflammation, namely microglia activation, production of pro-inflammatory cytokines and of growth factors such as BDNF; A2AR also limit the enhanced susceptibility for neuronal damage prompted by pro-inflammatory cytokines, which seems to require A2AR up-regulation and recruitment of novel transducing pathways. Overall, this suggests that A2AR plays a dual role controlling both microglia activation and the feed-forward impact of neuroinflammation on neurons. The recent design of two transgenic lines with tissue-selective deletion of A2AR in microglia cells (LysM-Cre-based) and in glutamatergic neurons (NEX-Cre-based) opens new exciting possibilities to disentangle the role of A2AR in controlling the bolstering of neuroinflammation and its impact on the functioning of neuronal circuits.

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